This invention is related to percutaneous biological fluid sampling and analyte measurement, and more particularly to constituent transfer mediums to facilitate sampling of biological fluid.
The detection of analytes in biological fluids is of ever increasing importance. Analyte detection assays find use in a variety of applications, including clinical laboratory testing, home testing, etc., where the results of such testing play a prominent role in the diagnosis and management of a variety of disease conditions. Common analytes of interest include glucose, e.g., for diabetes management, cholesterol, and the like.
A common technique for collecting a sample of blood for analyte determination is to pierce the skin at least into the subcutaneous layer to access the underlining blood vessels in order to produce localized bleeding on the body surface. The accessed blood is then collected into a small tube for delivery and analyzed by testing equipment, often in the form of a hand-held instrument having a reagent test strip onto which the blood sample is placed. The fingertip is the most frequently used site for this method of blood collection due to the large number of small blood vessels located therein. This method has the significant disadvantage of being very painful because subcutaneous tissue of the fingertip has a large concentration of nerve endings. It is not uncommon for patients who require frequent monitoring of an analyte to avoid having their blood sampled. With diabetics, for example, the failure to frequently measure their glucose level on a prescribed basis results in a lack of information necessary to properly control the level of glucose. Uncontrolled glucose levels can be very dangerous and even life-threatening. This technique of blood sampling also runs the risk of infection and the transmission of disease to the patient, particularly when done on a high-frequency basis. The problems with this technique are exacerbated by the fact that there is a limited amount of skin surface that can be used for the frequent sampling of blood.
To overcome the disadvantages of the above technique and others that are associated with a high degree of pain, certain analyte detection protocols and devices have been developed that use micro-needles or analogous structures to access the interstitial fluid within the skin. The micro-needles are penetrated into the skin to a depth less than the subcutaneous layer so as to minimize the pain felt by the patient. The interstitial fluid is then sampled and tested to determine the concentration of the target constituent. The concentration of a constituent within the interstitial fluid is representative of the concentration of that constituent in other bodily fluids, such as blood.
Conventional micro-needle sampling systems have a drawback in that, because the interstitial fluid inside the human body is at a negative pressure of about 6 mm/Hg, some kind of mechanical or vacuum means is often used in conjunction with the micro-piercing members.
For example, International Patent Application WO 99/27852 discloses the use of vacuum pressure and/or heat to increase the availability of interstitial fluid at the area of skin in which the vacuum or heat is applied. The vacuum pressure causes the portion of skin in the vicinity of the vacuum to become stretched and engorged with interstitial fluid, facilitating the extraction of fluid upon entry into the skin. Another method is disclosed wherein a localized heating element is positioned above the skin, causing interstitial fluid to flow more rapidly at that location, thereby allowing more interstitial fluid to be collected per given unit to time.
Still other detection devices have been developed which avoid penetration of the skin altogether. Instead the outermost layer of skin, called the stratum corneum, is xe2x80x9cdisruptedxe2x80x9d by a more passive means to provide access to or extraction of biological fluid within the skin. Such means includes the use of oscillation energy, the application of chemical reagents to the skin surface, etc. For example, International Patent Application WO 98/34541 discloses the use of an oscillation concentrator, such as a needle or wire, which is positioned at a distance from the skin surface and caused to vibrate by means of an electro-mechanical transducer. The needle is immersed in a receptacle containing a liquid medium placed in contact with the skin. The mechanical vibration of the needle is transferred to the liquid, creating hydrodynamic stress on the skin surface sufficient to disrupt the cellular structure of the stratum corneum. International Patent Applications WO 97/42888 and WO 98/00193 also disclose methods of interstitial fluid detection using ultrasonic vibration.
Thus, despite the work that has already been done in the area of analyte testing, there is a continued interest in the identification of new analyte detection methods that more readily meet the needs of the relevant market. Of particular interest would be the development of a minimally invasive analyte detection system that is practical, manufacturable, accurate and easy to use, as well as safe and efficacious.
U.S. Patents of interest include: U.S. Pat. Nos. 5,582,184, 5,746,217, 5,820,570, 5,942,102, 6,091,975 and 6,162,611. Other patent documents and publications of interest include: WO 97/00441, WO 97/42888, WO 98/00193 WO 98/34541, WO 99/13336, WO 99/27852, WO 99/64580, WO 00/35530, WO 00/57177 and WO 00/74765A1.
Percutaneous biological fluid sampling and analyte measurement systems and devices, as well as methods for using the same are provided by the subject invention. A feature of the subject devices is the presence of a constituent transfer medium that samples and transfers at least the target constituent(s) of biological fluid accessed within the skin to an electrochemical cell for measurement of the targeted constituent(s) within the fluid sample. The present invention finds use in accessing biological fluids such as blood and interstitial fluid, and in the detection and measurement of various analytes, e.g., glucose, cholesterol, electrolytes, pharmaceuticals, or illicit drugs, and the like, which are present in the accessed biological fluid. The present invention is especially well-suited for the sampling and measurement of interstitial fluid constituents such as glucose.
In general, the subject sampling and measurement devices include an elongated skin-piercing or skin-penetrating means to provide access to the biological fluid, at least one sampling means in the form of a constituent transfer medium, and a measuring means in the form of an electrochemical measurement cell in fluid communication with the constituent transfer medium.
The skin-penetrating means includes at least one micro-needle defining a substantially annular bore or channel through at least a portion of the interior of the micro-needle structure and having an access opening at a distal end through which one or more biological fluid constituents enter into the device. In many embodiments, the skin-piercing means comprises an array of such micro-needles.
The electrochemical measurement cell comprises spaced-apart working and reference electrodes positioned within and/or further defining the micro-needle structure. The area between the electrodes is defined as the reaction zone in which the actual measurement of analyte concentration takes place. In certain embodiments, the electrode pair are co-axially positioned and concentrically-spaced from each other, wherein at least the outer electrode has a hollow, cylindrical configuration and, at least in part, defines the micro-needle structure. The inner electrode is positioned within the cylindrical wall of the outer electrode and may also have a cylindrical configuration, either as hollow cylinder filled with a center core material or as a solid cylinder. In other embodiments, the electrochemical cell defines the proximal end of the micro-needle structure in the form of two parallel-spaced planes positioned substantially transverse to the longitudinal axis of the micro-needle.
In operation, one of the electrodes of the electrochemical cell is used as the reference electrode by which an input reference signal is provided to the sensor from a signal generating means. The other electrode operates as a working electrode that provides an output signal from the sensor to a signal receiving means. Preferably, the reference electrode is located at the bottom and the working electrode is located at the top of the device. This output signal represents the concentration of the target analyte in accessed biological fluid.
A redox reagent system or material may be used within the electrochemical cell to facilitate targeting the analyte(s) of interest. The particular redox reagent material used is selected based on the analyte targeted for measurement.
The constituent transfer medium of the sampling means occupies the area between the two electrodes, referred to as the reaction zone, and at least a portion of each micro-needle channel. The constituent transfer medium is made of a hydrogel or gel material or matrix that is hydrophilic and has an affinity for ionic and anionic particles within biological fluid. Optionally, the gel matrix may be configured to transfer only particles having a molecular weight less than a specified weight. The gel acts to transfer at least the targeted biological fluid constituent(s) present at the access opening of a micro-needle into the reaction zone. In other words, the targeted constituent(s) migrates through the gel matrix until equilibrium is reached between the concentration of the constituent(s)within the tissue and the concentration of the constituent(s) within the gel matrix. As compared to a hollow micro-needle which relies solely on capillary force that it exerts on the biological fluid as a means to transfer the biological fluid to the electrochemical cell, the subject constituent transfer medium may be configured (i.e., presented in a fully saturated state) to eliminate the transfer of water and other fluids contained within the accessed biological fluid, while transferring only constituents of the biological fluid. It is the configuration of the electrochemical cell that selects the targeted constituent(s) from the remaining constituents for testing.
The gel matrix of the present invention is characterized by a concentration gradient that changes in accordance with a first order system. This allows calculation of ionic and non-ionic element concentrations by means of the exponential characteristics of the first order system.
The subject sensor devices may function as a part of an analyte sensing system that includes a means for controlling the sensor device. Specifically, a control unit is provided in which the control means is electrically coupled with the sensor device and functions to generate and send input signals to the electrochemical cell and to receive output signals from the cell. These functions, among others, are performed by a software algorithm programmed within the control unit that automatically calculates and determines the concentration of the target analyte in the biological sample upon receipt of an output signal from the electrochemical cell.
An exemplary method of the subject invention involves using at least one subject sensor device comprising one or more hollow micro-needles having an open distal end defining a constituent transfer pathway to an integrally-coupled electrochemical cell. A hydrophilic gel material fills the interior of the micro-needle and the electrochemical cell. The micro-needle is inserted into the skin to a selected depth, preferably to a depth that avoids contacting nerve endings and blood vessels. Next, the at least the targeted constituent(s) of the biological fluid present at the open distal end of the micro-needle is wicked into the gel material and transferred into the reaction zone of the electrochemical cell. An electrochemical measurement is then made between the working and reference electrodes that provides an electrical signal that is representative of the concentration the constituent in the sample. The concentration of the constituent in the patient""s blood is then derived from the obtained electrical signal. A numerical value representing this concentration may then be displayed on a display unit. A software algorithm that is part of the device, e.g., programmed into a control unit present in the device, may be employed to determine the signal levels transmitted by the control unit to the cell and for deriving the concentration level of the target analyte.
The subject devices, systems and methods find use in analyte concentration measurement of a variety of analytes and are particularly suited for use in the measurement of glucose concentration in interstitial fluid.